Abstract 17762: Osteopontin is Associated with Vascular Smooth Muscle Cell Autophagy in Bicuspid Aortic Valve Aneurysm
Ascending thoracic aortic aneurysm (TAA) develops in about 35% of subjects with bicuspid aortic valve (BAV). It is a congenital disorder of unknown cause with a population prevalence of 1%-2%. In previous studies we have shown up-regulation of vascular smooth muscle cell (VSMC) apoptosis and cystic medial necrosis in the tunica media of BAV aneurysm tissue similar to Marfan syndrome (MFS) aortic aneurysm. In BAV but not MFS aneurysm we have identified in electron microscopy studies autophagy as an additional cause of VSMC loss. Osteopontin (OPN) exerts pro-inflammatory effects on VSMCs and has recently been shown to stimulate autophagy and down-regulate Notch1. In this study we examined apoptosis, autophagy and expression of OPN in human aortic aneurysm tissue. Thoracic aortic aneurysm tissue was obtained from subjects with BAV (6M; 5F; 31-75yr) and Marfan syndrome (MFS; 5M; 3F; 26-76yr) at the time of surgery. Normal thoracic aorta (TAC; 1M; 4F; 22-56yr) was obtained from organ donors. The number of VSMCs and apoptotic VSMCs (using caspase-3 marker) in sections of aortic tissue (20 fields at 400x /subject) were compared with counts in normal tissues. The number of VSMCs in both BAV and MFS aneurysm was reduced compared to normal aorta (BAV: 15.6±3.4, mean±SD; MFS 22.4±2.9; TAC: 30.7±8.9; p<0.05). There was a significant difference in the number of apoptotic VSMCs in BAV compared to MFS (BAV: 3.4±1.2; MFS: 7.6±2.3; p<0.05). The finding of with fewer apoptotic VSMCs in BAV compared to MFS indicates an important cause of cell death in BAV in addition to apoptosis. On immunohistochemistry localised patches of high intensity intracellular OPN were present in BAV aortic media in all subjects consistent with areas of autophagy identified on previous electron microscopy. In MFS there was low level diffuse staining of extracellular OPN associated with areas of calcification. In normal tissue there was low level diffuse expression of OPN. The studies suggest autophagy mechanisms contribute to cell death in BAV in contrast to absence of autophagy in MFS. Up-regulation of OPN in association with autophagy in BAV may be related to recent reports of abnormal Notch1 signalling in BAV.
- © 2012 by American Heart Association, Inc.